Diabetes is exploding globally and in the US, driven by an increasingly sedentary life-style, poor nutritional habits and obesity. It has been estimated that type-2 diabetes will soon assume a pandemic status globally. An analog of glucagon-like peptide-1 (GLP-1), Exenatide, is an approved drug to treat type-2 diabetes in humans. However, both GLP-1 and Exenatide are rapidly cleared, which necessitates twice-daily injection of the drug, and also leads to undesirable side-reactions such as nausea, and hence limits both the efficacy of the drug and its widespread adoption. Longer acting formulations of GLP-1 analogs and other peptide drugs are hence needed to improve drug efficacy and increase patient compliance. Motivated by this rationale, the overall objective of this proposal is to develop a novel biomaterials platform technology to enhance the half-life of GLP-1, by the in vivo formation of an injectable drug depot, which we have named Protease Operated Depots (PODs). Our design of PODs is implemented by the fusion between a thermally sensitive elastin-like polypeptide (ELP) that is soluble at room temperature but forms a viscous coacervate depot upon injection at body temperature, and repeats of GLP-1 that have recognition sites for a specific protease, embedded between repeats of the peptide drug. This strategy leverages our previous experience in biomaterials development of recombinant ELP-based biopolymers that can be designed to undergo a phase transition in vivo, driven by body heat to form a highly viscous coacervate with long retention upon injection. The specific aims are: (1) to synthesize a library of PODs with varied ELP MW and transition temperature, number of GLP-1 repeats per oligomer, and different protease recognition sequence between the GLP-1 repeats; (2) investigate the in vivo pharmacokinetics of PODs in a mouse model of type-2 diabetes to identify a subset of PODs that may be useful for once-a-week and once-a-month injection; and (3) carry out in vivo efficacy studies of a subset of these PODs. The outcome of these studies will be demonstration of PODs for the sustained delivery of GLP-1 with tunable injection frequency, as dictated by clinical need. Given the rise of type-2 diabetes in children and adolescents, an injectable formulation of GLP-1 that can be injected subcutaneously through a narrow gauge needle with a once-a-week or preferably once-a-month duration of efficacy, as proposed here will, we believe, also provide the necessary attributes for effective treatment of this sub-population of patients. More broadly, we envision PODs as a broadly applicable biomaterials platform technology to improve the pharmacokinetics and bioavailability, and hence efficacy of a large subset of peptide drugs that are currently in the clinical pipeline.